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Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome. PLoS One 2015;10(10):e0133994

Date

10/16/2015

Pubmed ID

26465331

Pubmed Central ID

PMC4605610

DOI

10.1371/journal.pone.0133994

Scopus ID

2-s2.0-84949034112   7 Citations

Abstract

Small Heat Shock Proteins (sHSPs) are molecular chaperones that transiently interact with other proteins, thereby assisting with quality control of proper protein folding and/or degradation. They are also recruited to protect cells from a variety of stresses in response to extreme heat, heavy metals, and oxidative-reductive stress. Although ten human sHSPs have been identified, their likely diverse biological functions remain an enigma in health and disease, and much less is known about non-redundant roles in selective cells and tissues. Herein, we set out to comprehensively characterize the cardiac-restricted Heat Shock Protein B-2 (HspB2), which exhibited ischemic cardioprotection in transgenic overexpressing mice including reduced infarct size and maintenance of ATP levels. Global yeast two-hybrid analysis using HspB2 (bait) and a human cardiac library (prey) coupled with co-immunoprecipitation studies for mitochondrial target validation revealed the first HspB2 "cardiac interactome" to contain many myofibril and mitochondrial-binding partners consistent with the overexpression phenotype. This interactome has been submitted to the Biological General Repository for Interaction Datasets (BioGRID). A related sHSP chaperone HspB5 had only partially overlapping binding partners, supporting specificity of the interactome as well as non-redundant roles reported for these sHSPs. Evidence that the cardiac yeast two-hybrid HspB2 interactome targets resident mitochondrial client proteins is consistent with the role of HspB2 in maintaining ATP levels and suggests new chaperone-dependent functions for metabolic homeostasis. One of the HspB2 targets, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), has reported roles in HspB2 associated phenotypes including cardiac ATP production, mitochondrial function, and apoptosis, and was validated as a potential client protein of HspB2 through chaperone assays. From the clientele and phenotypes identified herein, it is tempting to speculate that small molecule activators of HspB2 might be deployed to mitigate mitochondrial related diseases such as cardiomyopathy and neurodegenerative disease.

Author List

Grose JH, Langston K, Wang X, Squires S, Mustafi SB, Hayes W, Neubert J, Fischer SK, Fasano M, Saunders GM, Dai Q, Christians E, Lewandowski ED, Ping P, Benjamin IJ

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Apoptosis
Computational Biology
Cytosol
Energy Metabolism
Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)
HSP27 Heat-Shock Proteins
Heart
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mitochondria
Molecular Chaperones
Muscle Development
Myocardium
Oxidation-Reduction
Oxidative Stress
Phenotype
Proteomics
Reperfusion Injury
Troponin I
Two-Hybrid System Techniques
alpha-Crystallin B Chain
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a